Green-sourced polyphenols for ocular health: A sustainable NADES-based approach to dry eye disease treatment

Dry Eye Disease (DED) is a multifactorial ocular disorder driven by inflammation, oxidative stress, and microbial imbalance. In pursuit of a sustainable therapeutic alternative, this study developed a novel ophthalmic hydrogel (HAZ@gel) incorporating polyphenol-rich hazelnut cuticle (HC) extracts obtained via Natural Deep Eutectic Solvents (NADES), embedded into a Carbopol-based matrix. A wide panel of NADES combinations was screened to optimize extraction efficiency, resulting in acid-based NADESs delivering the highest total phenolic content with favorable physicochemical properties. The HAZ@gel formulation demonstrated excellent biocompatibility and sustained polyphenol release, along with significant antioxidant and anti-inflammatory activity in hyperosmotic-stressed human corneal epithelial cells, a validated in vitro DED model. The formulation also exerted antimicrobial effects against Bacillus subtilis and Escherichia coli , further supporting its multifunctional potential. This work exemplifies a circular economy strategy by valorizing agro-industrial waste through green extraction and eco-friendly formulation, proposing a biodegradable and efficacious ocular therapy aligned with sustainable pharmaceutical innovation. • A biodegradable ophthalmic hydrogel (HAZ@gel) was developed using polyphenol-rich hazelnut cuticle waste extracts. • Green extraction with acid-based NADES improved polyphenol recovery and extract stability. • The HAZ@gel formulation showed potent antioxidant and anti-inflammatory effects in a hyperosmotic stress model of Dry Eye Disease. • Sustained release and biocompatibility were achieved using a thermoresponsive Carbopol matrix. • This study integrates green chemistry, circular economy, and eco-innovation principles in ophthalmic drug development.